Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides
Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides
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使用化学限制肽靶向恶性疟原虫 UCHL3 泛素水解酶
DOI：
10.1101/2024.01.11.575158
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
King H
中科院分区：
文献类型：
--
作者：
King H
泛素-蛋白酶体系统对所有真核生物都是必不可少的，也被证明对寄生虫的生存至关重要，包括恶性疟原虫，它是最致命的疟疾的病原体。尽管泛素-蛋白酶体途径在寄生虫的整个生命周期中起着核心作用，但目前还不存在针对介导泛素附着和移除的个别酶的特定抑制剂。颠覆P的能力。恶性疟原虫在多个发育阶段的生长特别有吸引力，因为这可能既可以防止由无性分裂的寄生虫引起的疾病病理，也可以防止由有性分化的寄生虫介导的传播。去泛素化酶PfUCHL3是一种必不可少的蛋白质，在人类和蚊子的发育阶段都有转录。PfUCHL3的活性部位与人类UCHL3以及其他UCH结构域的酶有很高的同源性，因此很难用传统方法进行药物治疗。在这里，我们应用快速信使核糖核酸展示技术，并鉴定出能够与PfUCHL3结合的具有纳摩尔亲和力的限制性多肽。这两个先导肽对PfUCHL3和HsUCHL3的脱泛素酶活性有选择性的抑制作用。核磁共振波谱显示，这些多肽并不是通过与活性部位结合来发挥作用的，而是通过阻断泛素底物的结合来发挥作用的。我们证明，这种方法可以用来靶向疟原虫泛素途径中的基本蛋白质-蛋白质相互作用，使化学受限的多肽能够作为一类新的抗疟疾治疗药物应用。
The ubiquitin–proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, includingPlasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin–proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disruptP. falciparumgrowth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein–protein interactions within thePlasmodiumubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
DOI：
10.1073/pnas.2003086117
发表时间：
2020-10-27
影响因子：
11.1
作者：
Patel K;Walport LJ;Walshe JL;Solomon PD;Low JKK;Tran DH;Mouradian KS;Silva APG;Wilkinson-White L;Norman A;Franck C;Matthews JM;Guss JM;Payne RJ;Passioura T;Suga H;Mackay JP
通讯作者：
Mackay JP
DOI：
--
发表时间：
2020
期刊：
IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology
影响因子：
--
作者：
Leah G. Helton;E. Kennedy
通讯作者：
E. Kennedy
影响因子：
4.8
作者：
Artavanis-Tsakonas, Katerina;Weihofen, Wilhelm A.;Ploegh, Hidde L.
通讯作者：
Ploegh, Hidde L.